tbuckley/cabot-search huggingface dataset:
Abstract 10921: Efficacy and Safety of Ongericimab in Chinese Patients With Homozygous Familial Hypercholesterolemia
Authors: Jie Lin, Jiyan Chen, Ruiyan Zhang, Jingfeng Wang, Xuelian Bai, Hui Yan, Jianjun Yu, Sheng Yao, hui feng, Jie Lin
Journal: Circulation (2022)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extremely high low-density lipoprotein cholesterol (LDL-C) levels that contributes to atherosclerotic cardiovascular disease and death, even in adolescent. Ongericimab, a monoclonal antibody against human proprotein convertase subtilisin/kexin type 9 (PCSK9), inhibits PCSK9-mediated degradation of LDL receptor (LDLR), and reduces LDL-C by 58.3-66.5% in Chinese patients with hyperlipidemia. Due to the high genetic heterogeneity of HoFH, the LDL-C lowering effect of Ongericimab remains elusive in Chinese population. This is the first study to assess the efficacy and safety of anti-PCSK9 antibody in Chinese patients with HoFH. Methods: This is a single arm, open-label phase 2 study. 31 patients (aged ≥12 years) with HoFH diagnosed by clinical or genetic criteria, on stable lipid-lowering therapies for ≥4 weeks, were enrolled to receive subcutaneous Ongericimab 450 mg every 4 weeks for 52 weeks. The primary endpoint was percentage change in LDL-C from baseline at week 12. Results: At the time of this interim analysis, 30 out of 31 patients completed 12 weeks treatment. All patients were on statins (77.4% on high intensity statin) and the mean (SD) baseline LDL-C was 8.6 (3.1) mmol/L. The least squares mean percentage change in LDL-C from baseline was -12.6% (95% CI: -19.7%, -5.6%; p=0.001) at week 12. Further analysis based on residual LDLR activity, the mean (SD) LDL-C change from baseline was -21.7 (28.0)% in 14 patients with defective LDLR (at least one defective allele) and -1.4 (9.6)% in 7 patients with negative LDLR (at least one negative allele), respectively (Figure 1). No serious side effects were reported. Conclusion: Ongericimab was well tolerated and significantly reduced LDL-C levels in Chinese patients with HoFH. Patients with defective LDLR demonstrated better response than those with negative LDLR.
Abstract 10789: Disruption of Stromal Interaction Molecule 1 in Immune Regulatory T Cells Protects Vascular Endothelial Function in Renovascular Hypertension
Authors: Khalid Matrougui, BALAJI SRINIVAS, Kiran Alluri, Jacob D O'Regan, Souad Belmadani
Journal: Circulation (2022)

Introduction &amp; Hypothesis: Microvascular dysfunction in renovascular hypertension is a major risk factor for cardiovascular diseases. However, the underlying mechanism of vascular endothelial dysfunction in renovascular hypertension is not fully understood. Here, we sought to determine the role and impact of the stromal interaction molecule 1 (STIM1) knockout in immune regulatory T cells (Stim1 Treg-/- ) in renovascular hypertension-induced vascular endothelial dysfunction. Methods: Mice were divided into four groups. Group 1 and 2: Stim1 flx/flx male and female mice with and without 2-kidney-1-clip (2K1C) surgery for four weeks. Group 3 and 4: Stim1 Treg-/- male and female mice with and without 2K1C for four weeks. We measured body weight, arterial blood pressure, cardiac hypertrophy, lung edema, inflammation, fibrosis, and assessed microvascular endothelial function. Results: Stim1 flx/flx both male and female mice subjected to 2K1C for four weeks develop hypertension, cardiac hypertrophy, lung edema, low running performance, and vascular dysfunction. Interestingly, the disruption of STIM1 in Treg cells in both male and female mice protected from 2K1C-induced hypertension, cardiac hypertrophy, and lung edema. Moreover, microvascular endothelial function was also protected in both groups. Conclusion: Our data illustrate that STIM1 in immune Treg cells has s significant impact in renovascular hypertension-induced cardiovascular complications. Thus, targeting STIM1 in Treg cells could be a potential therapeutic approach to protect from renovascular hypertension-induced cardiovascular diseases.
Abstract 10901: Differential Burden of Prediabetes and Diabetes Among Asians Subgroups in a Large US Healthcare System
Authors: William Vicks, Joan C Lo, Jamal S Rana, Nancy Gordon, Nirmala D Ramalingam
Journal: Circulation (2022)

Introduction: We previously reported that Chinese, Filipino, and South Asian adults have higher prevalence of prediabetes (PreDM) than non-Hispanic White (White) adults, with nearly twice the burden in healthy BMI ranges. This study further examines the differential burden of diabetes (DM) in these Asian subgroups using Asian specific BMI categories. Methods: 283,110 White, 33,263 Chinese, 38,766 Filipino, and 17,959 South Asian adults aged 45-64y in a 2016 Northern California health plan with height and weight were examined. PreDM and DM were classified based on lab data, diagnoses, or DM treatment. Modified log Poisson regression was used to determine Asian group vs. White prevalence ratios (PRs) for DM and preDM, adjusted for age and BMI within healthy weight, overweight, and obesity ranges (BMI 18.5 to &lt;25, 23 to &lt;30, ≥30 kg/m2 for Whites; BMI 18.5 to &lt;23, 23 to &lt;27.5, ≥27.5 kg/m2 for Asians). Results: Across all BMI categories, DM prevalence was higher for the Asian groups than White adults. DM prevalence was also higher for Filipino and South Asian vs White than Chinese vs White, especially at healthy BMI levels. PRs for South Asian men/women at healthy BMI were 1.8/2.8 for preDM and 5.9/8.0 for DM (Figure). PRs for Filipino men/women at healthy BMI were 1.8/2.6 for preDM and 5.0/7.5 for DM, respectively. For Chinese men/women at healthy BMI, the PRs for preDM were similar (2.1/2.9) to the other Asian groups, but the PRs for DM were lower (2.1/3.4). Conclusion: The largest difference in DM prevalence relative to White adults was observed in the healthy BMI range for South Asian and Filipino adults. While PreDM risk in these 2 groups was similar to the preDM risk in Chinese compared with White adults at healthy BMI, their DM risk was 5-8 times greater than White adults at healthy BMI. Our data emphasize the disproportionate metabolic risk among middle-aged adults of different Asian groups and underscore the need for DM screening among high-risk Asian subgroups at healthy BMI levels.
Abstract 10586: CREG1-FBXO27-LAMP2 Axis Promotes Autophagy Function of Cardiomyocytes and Alleviates Diabetic Cardiomyopathy
Authors: Dan Liu, Ruinan Xing, Quanyu Zhang, Xiaoxiang Tian, Yanping Qi, haixu song, Yanxia Liu, Haibo Yu, Xiaolin Zhang, Chenghui Yan, Yaling Han
Journal: Circulation (2022)

Introduction: Diabetic cardiomyopathy is a chronic complication of diabetes in the absence of coronary artery disease, arterial hypertension and valvular disease. Autophagy plays an important role in the development of diabetic cardiomyopathy. Cellular repressor of E1A-stimulated genes 1 (CREG1) is an important myocardial protective factor. The aim of this study was to investigate the effects and mechanisms of CREG1 in diabetic cardiomyopathy. Methods: Male C57BL/6J mice, CREG1 transgenic mice, and CREG1 cardiac-specific knockout mice were used to establish a type 2 diabetic model. Small animal ultrasound, Masson’s staining, and western blotting were used to evaluate cardiac function, myocardial fibrosis and autophagy. Neonatal mouse cardiomyocytes (NMCMs) were isolated and cultured. NMCMs were infected with CREG1- overexpressing adenovirus or small interfering RNA, followed by stimulation with palmitic acid (PA), real-time PCR, western blotting and immunofluorescence staining were used. Results: CREG1 protein expression was decreased in the myocardium of diabetic cardiomyopathy. CREG1 deficiency in the heart aggravated cardiac dysfunction, cardiac hypertrophy, and fibrosis in mice with diabetic cardiomyopathy, accompanied by aggravated autophagy dysfunction. CREG1 overexpression improved cardiac function and ameliorated cardiac hypertrophy and fibrosis in diabetic cardiomyopathy, by improving autophagy. CREG1 protein expression was decreased in PA-stimulated NMCMs. CREG1 knockdown aggravated cardiomyocyte hypertrophy and inhibited autophagy, which were reversed by resveratrol treatment. Conversely, CREG1 overexpression inhibited cardiomyocyte hypertrophy and improved autophagy, which were reversed by chloroquine or bafilomycin A1 treatment. Overexpression of LAMP2 reversed the effect of CREG1 knockdown on the PA-induced inhibition of cardiomyocyte autophagy. CREG1 inhibited the LAMP2 protein degradation by inhibiting the expression of F-box protein 27 (FBXO27). Conclusions: CREG1-FBXO27-LAMP2 axis alleviated diabetic cardiomyopathy by promoting cardiomyocyte autophagy. Our findings might help clarify new roles of CREG1 in the development of diabetic cardiomyopathy.
Abstract 10889: Unplanned Limb Revascularization With Rivaroxaban versus Placebo in Patients With Critical Limb Ischemia After Endovascular and Surgical Treatment: Insights From Voyager Pad
Authors: Shea E Hogan, Manesh R Patel, Sebastian Debus, Mark Nehler, Sonia S Anand, Mario Enrico Canonico, Connie N Hess, R. Kevin Rogers, Judith A Hsia, Eva Muehlhofer, Lloyd P Haskell, Scott D Berkowitz, Rupert Bauersachs, Marc P Bonaca
Journal: Circulation (2022)

Introduction: Patients with critical limb ischemia (CLI) have a class I indication for lower extremity revascularization (LER) by either endovascular or surgical approach. A common complication is recurrent arterial occlusion requiring unplanned index limb revascularization (UILR). VOYAGER PAD established the efficacy of rivaroxaban in patients with symptomatic peripheral artery disease (PAD) after successful LER, including a reduction in UILR. Whether this benefit differs by LER approach for CLI is unknown. Hypothesis: Rivaroxaban reduces UILR regardless of LER approach for CLI. Methods: LER indication (CLI or claudication) and approach were captured at baseline. The primary composite endpoint was acute limb ischemia, major vascular amputation, MI, ischemic stroke or CV death. TIMI major bleeding was the primary safety outcome. UILR was a prespecified secondary outcome. A Cox proportional-hazards model was used to calculate hazard rations and 95% confidence intervals. Results: Among 6,564 participants randomized , 1,533 (23%) had CLI, of whom 696 (45%) and 837 (55%) underwent surgical and endovascular LER, respectively. CLI patients on rivaroxaban had fewer events at three years compared to those on placebo (HR 0.85). Efficacy of rivaroxaban for the primary endpoint (p-interaction 0.40) and safety (p-interaction 0.18) in CLI were consistent regardless of approach. On background therapy (aspirin in all, statins ~80%, DAPT ~50%), at a median of 28 months, UILR occurred in 26.2% and 14.3% after endovascular and surgical LER, respectively. Rivaroxaban significantly reduced UILR by 22% in patients with CLI (HR 0.78, p=0.019, Figure), with consistent benefits in those treated with endovascular and surgical LER (p-interaction 0.70). Conclusions: CLI patients have high rates of UILR after LER. Rivaroxaban reduced the rate of UILR in this population, regardless of endovascular or surgical approach.
Abstract 10230: Epidemiology of Early and Late Ventricular Assist Device Infections in Bridge-to-Transplant Patients: A Single Centre Experience
Authors: Ansh Goyal, Sara M Hockney, Rebecca Kumar, Rebecca Harap, Jane E Wilcox, Duc Thinh T Pham, Valentina Stosor
Journal: Circulation (2022)

Introduction: Bacterial infections are common after ventricular assist device (VAD) implantation. Better understanding of their epidemiology in bridge-to-transplant (BTT) pts will allow for improved infection prevention, management, and optimization for transplantation. Methods: We performed a retrospective cohort study of 42 BTT pts with VAD infections from 4/2006-10/2020. VAD-specific and VAD-related infections were characterized according to 2011 ISHLT definitions. Infections were classified as early if occurring ≤ 90 days, and late if occurring &gt;90 days after VAD implantation. Results: The prevalence of VAD infections among BTT pts was 23%, with 24% of those occurring early and 76% occurring late. Pts with infections were predominantly male (n=32, 76%) and white (n=30, 71%), with non-ischemic cardiomyopathy (n=22, 52%), and mean age at implantation of 52.7y. There were no significant differences in baseline characteristics between pts who developed early or late VAD infections (Table 1). Pts had VAD infections involving the bloodstream (n=22), driveline (n=22), pump (n=9), and pocket (n=3), with an additional 10 pts with possible endocarditis and 3 with sternal infections/mediastinitis. Most superficial driveline infections occurred more than 90 days after implantation (19 vs. 1, p=0.029). There were no significant differences in the incidence of early and late infection for the remainder of VAD-related infections reviewed (Table 2). Gram-negative organisms were responsible for the most infections (n=15), followed closely by Staphylococcus aureus (n=14); there was no significant difference in organisms causing early vs. late infection (Table 3). Conclusions: In this single center study of BTT pts over a 14-year period, superficial drive-line infections rarely occurred in the first 90 days post-VAD implantation. Gram-negative rods and Staphylococcus aureus were nearly equally responsible for most infections.
Abstract 10776: A Supervised Classification Model Detects Fontan Patients Based on Clinical Notes With Higher Accuracy Than ICD Codes
Authors: YUTING GAO, MOHAMMED A AL-GARADI, Wendy M Book, Lindsey Ivey, Fred H Rodriguez, Cheryl L Raskind-Hood, ABEED SARKER
Journal: Circulation (2022)

Introduction: The Fontan operation palliates single ventricle heart defects. As native anatomy varies, Fontan cases cannot always be identified by ICD9 or 10CM codes. Hypothesis: We sought to train and evaluate a supervised machine learning (ML) system to identify Fontan cases based on unstructured clinical notes in a large database. Methods: 160 adult Fontan patients from validated clinical data at a single tertiary referral center with available text notes were studied. The imbalanced data set had more non-Fontan cases than Fontan patients; thus we created multiple datasets with different positive : negative case ratios ranging from 1:2 to 1:10. We used stratified 80-20 training-testing splits of data. Vectorized representations of text notes were used as features. We trained a Support Vector Machine (SVM) model, mostly used for text classification, to identify Fontan cases from notes. For each dataset, we performed random 80-20 data splitting 10 times and reported average F 1 score (harmonic mean of recall/sensitivity &amp; precision/positive predictive value) over the positive class. Results: The model achieved a mean F 1 score of 0.95 for the positive class on the data split with 1:2 positive-negative ratio. Increasing data imbalance from 1:2 to 1:10 did not substantially impact performance. The mean F 1 score over all data splits was 0.94, and SD 0.01. We also computed precision, recall, and F 1 score of ICD codes to identify Fontan patients. Performance comparisons between ICD codes only and Natural Language Processing (NLP)/ML are in Table 1. Conclusions: A supervised classification model more effectively detects Fontan patients based on clinical notes with higher accuracy than ICD codes. The model is robust and insensitive to data imbalance. Findings suggest our model may work effectively in real-world data. Since the sensitivity of ICD codes is high but PPV is low, it may be beneficial to apply ICD codes as a filter prior to applying NLP/ML to improve performance.
Abstract 10389: Interleukin-1 Blockade With Anakinra Restores Cardiac Contractility Reserve and Exercise Capacity in a Mouse Model of Ischemic Heart Failure
Authors: Pratyush Narayan, Habeebah Vohra, Eleonora MEZZAROMA, Michelle Kim, Benjamin Van Tassel, Antonio Abbate, Stefano Toldo
Journal: Circulation (2022)

Background: Acute myocardial infarction (AMI) is associated with an intense inflammatory response promoting adverse cardiac remodeling, impaired cardiac reserve, and reduced exercise capacity, hallmarks of heart failure. Interleukin-1β (IL-1β) is the prototypical inflammatory cytokine that is increased in AMI and is sufficient to impair cardiac reserve when administered exogenously in mice. Whether blocking IL-1β signaling with recombinant IL-1 receptor antagonist, anakinra, can restore cardiac contractile reserve and improve exercise capacity in AMI is unknown. Methods: We induced ischemic heart failure due to large non-reperfused anterior AMI in mice via surgical permanent ligation of the left anterior descending artery via lateral thoracotomy in 10-week-old male CD1 mice (N=30, 32-37 g in weight) followed for 10 weeks. Anakinra was given as intraperitoneal injection of 10 mg/kg, 0.2 ml, for three consecutive days. Cardiac contractile reserve was measured assessing changes in left ventricular fractional shortening with isoproterenol challenges (N=5). A subgroup of mice that had been previously trained to run on treadmill were used to measure interval changes in exercise capacity 10 weeks after AMI and with three consecutive days of anakinra treatment (N=6). Data are presented as mean and standard error of mean. T-test for paired group analysis was used to compare values. Results: Cardiac contractile reserve was impaired at -10±5% and restored with anakinra given for three days to +49±11% (p=0.008). Exercise capacity was also significantly reduced with AMI at 191±39 m and restored to 247±46 m after anakinra treatment (p=0.03). Conclusion: Ischemic heart failure due to large non-reperfused AMI leads to a severe reduction in cardiac contractility reserve and exercise capacity that are reversed by IL-1 blockade with anakinra.
Abstract 102: Pharmacological Selective Inhibition Of Astrocyte Metabolism Improves Neurological Recovery After Cardiac Arrest In Rabbits
Authors: Estelle Faucher, Lidouren Fanny, Yara Abi Zeid Daou, Bijan Ghaleh, Renaud Tissier, Matthias Kohlhauer
Journal: Circulation (2022)

Introduction: Astrocytes promote cerebral inflammation during neuronal focal ischemic injury and lactate consumption by neurons. However, the physiopathological role of astrocytes remains to be established during cardiac arrest. Hypothesis: We hypothesized that inhibition of astrocytes metabolism by the citric acid cycle inhibitor fluorocitrate (FC) could improve the neurological recovery after a cardiac arrest. Methods: Anesthetized male New-Zealand rabbits randomly received an intrathecal injection of saline (Control) or FC (10 nmol/kg, “FC”) just before 10 min of ventricular fibrillation. In a first set of experiment (n=6 per group), we determined after resuscitation the cerebral consumptions of lactate and glucose by measuring their arteriojugular differences and the cerebral extracellular concentrations of several metabolites using a microdialysis probe during 4 h after cardiac arrest. In a second set of experiments (n=7 per group), neurological dysfunction was evaluated 24 h after cardiac arrest. Neuronal death and astrogliosis were quantified histologically. Results: In the first set of experiment, cerebral lactate consumption was significantly decreased in FC vs Control after cardiac arrest (6.4±2.3 and 14.5±4.7mmol/L/min, respectively). Extracellular concentration of lactate, pyruvate, glucose, glycerol or glutamate were similarin the 2 groups. In the second set of experiment, neurological outcome was significantly improved in FC vs Control at 24 h after cardiac arrest (19±7 vs 55±9% of neurological dysfunction score, respectively). Conclusions: Specific inhibition of citric acid cycle of astrocytes by FC is neuroprotective after cardiac arrest in rabbits.
Abstract 10578: St-Elevation Myocardial Infarction With Complete Heart Block in the Setting of Vagally Mediated Coronary Vasospasm
Authors: Thomas S Truglio, Esther Choi, Mariana L Henry, Kerrilynn Hennessey
Journal: Circulation (2022)

Introduction: This case identifies vagal tone as a paradoxical cause of coronary artery spasm, coinciding with complete heart block. It will additionally identify proper management in these cases. Clinical Presentation: A 53 year old male with a medical history of HIV not of ART, acute, infectious COVID-19 and late, latent syphilis admitted for malaise, found to have DLBCL. Following a routine blood draw the patient experienced acute chest and abdominal pain. Minutes later, while having a bowel movement he experienced syncope with heart rates in the 30s. EKG showed ST elevations in leads II, III, and aVF. Troponin-T was elevated to 0.15. Echocardiogram showed inferior wall hypokinesis. Coronary angiography showed non-obstructive right coronary disease. Cardiac MRI demonstrated no evidence of infiltrative disease or myocarditis. The patient experienced a similar episode the following morning, during blood draw, EKG and telemetry demonstrated complete heart block with ST elevations (image). This suggested vagal mediated AV block with coronary artery spasm (CAS). He was started on the anticholinergic hyoscyamine and amlodipine for vasodilation. Following initiation of therapy, the patient had no further episodes of chest pain or bradycardia. Discussion: While acetylcholine causes vasodilation via endothelial NO, interestingly, it can also lead to CAS. In the setting of vascular smooth muscle cell (VSMC) hyper-reactivity or high vagal tone, VSMC muscarinic receptors are activated leading to vasoconstriction. Vagal tone can cause both CAS with resulting STEMI as well as AV blockade resulting in high degree heart block (image). When ischemic symptoms are accompanied by AV block in the setting of high vagal tone, consider vagal mediated CAS. Calcium channel blockers such as amlodipine are used to manage CAS. When the suspected mechanism is vagal tone, management includes avoidance of precipitating factors and or anticholinergic premedication.